Children and caregiver proxy quality of life from peanut oral immunotherapy trials

Abstract Background Health‐related quality of life (HRQoL) is significantly and substantially reduced in individuals with peanut allergy due to many factors associated with unanticipated or potentially fatal reactions. Further insight on the impact of peanut oral immunotherapy in managing peanut allergy on HRQoL is needed. The aim of this analysis was to assess effects of peanut (Arachis hypogaea) allergen powder‐dnfp (PTAH), a biologic drug for peanut oral immunotherapy, on HRQoL from three phase 3 and two follow‐on trials of PTAH. Methods HRQoL assessments from participants aged 4–17 in the PALISADE (ARC003), ARC004 (PALISADE follow‐on), ARTEMIS (ARC010), RAMSES (ARC007), and ARC011 (RAMSES follow‐on) trials were included in this analysis. Responses on the Food Allergy Quality of Life Questionnaire (FAQLQ) and Food Allergy Independent Measure (FAIM) were evaluated by age group and respondent (self or caregiver proxy). Data were analyzed with descriptive statistics and Student t tests. Results Baseline FAQLQ and FAIM total scores appeared comparable between PTAH‐ and placebo‐treated participants. Self and caregiver proxy‐reported total scores on the FAQLQ for PTAH‐treated participants generally improved at trial exit versus baseline; FAIM total scores improved throughout all trials. The tendency for improvement in FAQLQ total scores from baseline for PTAH appeared larger in self versus caregiver proxy‐reports. Between treatment groups, PTAH was generally favored in the PALISADE and ARTEMIS trials; differences varied in the RAMSES trial based on age and respondent types. Conclusions PTAH for the management of peanut allergy in children appeared to have a beneficial effect on HRQoL in trials. Improvements were seen despite rigors of trial participation.


| INTRODUCTION
Health-related quality of life (HRQoL) is significantly reduced in patients with food allergy and their families. [1][2][3][4] The impact of food allergy extends beyond clinical outcomes such as number or severity of reactions to encompass fear/anxiety associated with unanticipated/ potentially fatal reactions. [1][2][3][4] Additionally, food allergy imposes restrictions and limitations on social activities and increases risk of depression or anxiety. 5 Understanding the impact of food allergy on HRQoL can guide policy making and healthcare resource allocation. 6,7 Peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; previously AR101; Palforzia ® ) is a biologic drug for peanut oral immunotherapy (OIT) approved in the United States and Europe to mitigate allergic reactions following accidental exposure to peanut in individuals aged 4-17 years with a confirmed diagnosis of peanut allergy. 8,9 PTAH demonstrated efficacy and safety in phase 2 and 3 trials. [10][11][12][13] Recently published guidelines for food allergy management acknowledge peanut OIT may induce desensitization in children allergic to peanut and support the use of a licensed/regulatory approved preparation for those aged 4-17 years with a confirmed diagnosis. 14,15 A systematic review of parent-reported measures of the psychosocial impact of food allergy on patients and their families found that practical, relevant, reliable, and valid parent-reported measures remain an unmet need. 16 Working with patients and their families and determining how support can be best provided requires a flexible approach. Regular follow-up is key to addressing changing psychosocial/dietary needs, monitoring allergy resolution, and evaluating treatment response. Additionally, comprehensive multidisciplinary or multiprofessional teams (including access to support from dietitians, psychologists, pharmacists, patient/caregiver/advocate organizations, and the food industry) are needed to optimize quality of life for individuals in complex situations. 17,18 Studies to date assessing HRQoL change following OIT demonstrate encouraging but mixed results. Whereas individual clinical and real-world studies have reported improvements with peanut OIT, 11,13,[19][20][21][22][23] a meta-analysis found no difference in HRQoL scores between OIT and placebo, 24 and a small study found parents, but not children, reported improvement. 25 Notably, providing psychological support to patients undergoing OIT and their families may improve HRQoL. 26 While several HRQoL instruments for various age groups and respondents (self vs. parent) were found to be reliable, valid, and responsive, evidence for sensitivity to change in response to treatment was limited, as was the determination of a clinical minimal important difference (MID). 27 The Food Allergy Quality of Life Questionnaire has undergone the most thorough validation process with psychometric property testing; the Food Allergy Independent Measure (FAIM) can be used concurrently as a correlating measure. 28 Previously, HRQoL data from ARTEMIS 11 demonstrated clinically meaningful improvements in PTAH-treated versus placebo-treated participants, and ARC004 13 showed clinically meaningful improvements in PTAH-treated participants, usually increasing with longer treatment duration on the FAQLQ and FAIM. The objective of this analysis was to assess effects of PTAH on HRQoL from multiple trials, including longer-term treatment and a larger population.
HRQoL assessment was a prespecified endpoint in all trials. For ARC004, only participants receiving PTAH daily (the approved dosage for maintenance treatment, 300 mg daily) 8,9 were included (cohorts 1 and 3A). Details of PALISADE, 10 ARC004, 12

| Assessments and endpoints
HRQoL assessments were conducted using the FAQLQ 29-31 and FAIM. 32 Items and domains on versions vary depending on the respondent (self or caregiver proxy) and age group of the participant.   HRQoL version (ie, the version for the next age range if the child was a year older at study end), so baseline and exit scores could be compared. A MID of 0.5 was used as a threshold. 33 Additional detail on scoring is found in the Supporting Information.

| Statistical analyses
Scores were summarized with descriptive statistics. To compare treatment and placebo group scores, a Student t test (paired or unpaired as appropriate) was used. Mean change was reported for within-group (PTAH) and between-group (PTAH vs. placebo) changes in scores from screening to exit visit. A change in score of ≥0.5 indicated an improvement of quality of life that reached or exceeded the MID. Statistical analyses were performed using Statistical Analysis Software, version 9.4 (SAS Institute, Inc.).

| PALISADE and ARC004
In PALISADE, baseline total FAQLQ and FAIM scores appeared comparable between PTAH-treated and placebo-treated participants ( Table 2). In PALISADE and ARC004, FAQLQ caregiver proxy-report scores of teenagers and self-report were higher on average than for caregiver proxy-report of younger children, regardless of treatment group. In PALISADE, FAIM scores for caregiver proxy-report were higher versus self-report.
In PALISADE, FAQLQ total score improvement from baseline in PTAH-treated participants was observed globally (ie, across all age groups and respondents), except for caregiver proxy-report of children aged 4-6 years ( Figure 2A). In PTAH-treated participants, improvement in FAIM total scores from baseline was observed globally ( Figure 2B).
The proportion of participants in PALISADE with MID in FAQLQ total scores was numerically higher for PTAH-treated versus placebo-treated participants globally, except for self-report by children aged 8-12 years; the MID in FAIM total scores was higher on average across age groups and respondents. In ARC004, the findings for MID in FAQLQ and FAIM total scores appeared variable among age groups and respondents in each cohort.
Comparisons between PTAH-treated and placebo-treated participants on FAQLQ and FAIM total scores show point estimates favoring PTAH; however, 95% confidence intervals were wide ( Figure 3A,B).

| ARTEMIS
Baseline total scores for FAQLQ and FAIM followed the same pattern as described above for PALISADE and ARC004 ( Table 2). Improvement in FAQLQ and FAIM total scores from baseline in PTAH-treated participants was observed globally (Figure 2A,B).
Proportions of participants who met or exceeded MID for FAQLQ total scores were higher for PTAH-treated than placebotreated participants globally, except for the caregiver proxy-report for children aged 13-17 years (lower) and 4-6 years (slightly higher). Among self-report for age groups 8-12 and 13-17 years, proportions of PTAH-treated participants with MID were~30 percentage points higher than for placebo-treated participants. The proportion who met or exceeded MID for FAIM total scores trended toward PTAH versus placebo.
Globally for FAQLQ total scores, PTAH differed compared with placebo with this difference most robust for self-report by children aged 8-12 years ( Figure 3A). For FAIM total scores, PTAH was different compared with placebo globally, the difference appearing most robust for self-report by children aged 13-17 years ( Figure 3B).

| RAMSES and ARC011
In RAMSES, baseline FAQLQ and FAIM total scores were comparable in PTAH-treated and placebo-treated participants in each age group and by respondent ( Table 2). In both RAMSES and ARC011, FAQLQ scores for the caregiver proxy-report of teenagers and self-report trended higher versus caregiver proxy-report of younger children.
FAIM scores for the caregiver proxy-report were slightly higher than for self-report in RAMSES and ARC011.
In RAMSES, FAQLQ and FAIM total score improvement in PTAH-treated participants was observed globally (Figure 2A,B). In ARC011, FAQLQ and FAIM total score improvement was observed globally and the magnitude of improvement generally appeared greater than in RAMSES.
In RAMSES, proportions of participants with MID in FAQLQ total scores appeared higher for placebo-treated versus PTAH-treated participants. In ARC011,~40% or more of participants had MID in FAQLQ and FAIM total scores. In RAMSES, proportions of participants with MID in FAIM total scores appeared variable.
For FAQLQ total scores, the difference between treatment groups appeared to favor placebo among self-reports ( Figure 3A).
Results for FAIM total scores had wide 95% confidence intervals ( Figure 3B).

| Descriptive analysis: Comparisons across trials
Across parent trials (PALISADE, ARTEMIS, and RAMSES), history of prior reaction to peanut and concurrent asthma or other food allergy were broadly comparable; sensitivity to peanut appeared higher in the RAMSES trial (Table S1). Across all trials, baseline FAQLQ total scores generally appeared similar. Caregiver proxies responding for teenagers appeared to have higher mean scores than for children aged 4-6 years; children seemed to have higher mean scores than for caregiver proxies responding for them. Self-and caregiver proxyreported FAQLQ total scores showed trends toward greater improvements in those who received PTAH for at least 9 months versus placebo (PALISADE and ARTEMIS). After~6 months of PTAH treatment (RAMSES), this trend toward improvement was only observed in caregiver proxy-reported FAQLQ total scores for the youngest participants aged 4-6 years.
Regarding change in FAQLQ total scores from baseline for active treatment, a tendency toward improvement (ie, reduction) in scores was observed and appeared larger in self-reports. Selfreported FAQLQ total scores for participants aged 8-12 years for caregiver proxies for children 13-17 years and "allergy avoidance and dietary restrictions" and "risk of accidental exposure" for children 8-12 years in the ARTEMIS trial. Curiously, placebo showed more improvement on "risk of accidental exposure" in the RAMSES trial (Table S2).
The greatest improvements in FAIM total scores were seen in PTAH-treated participants aged 13-17 years. Domains favoring PTAH over placebo in randomized, controlled trials pertained to the risk of severe reaction and death (  As reducing the psychosocial impact of food allergy has been identified as a key research priority, reliable and valid instruments and measures are needed to determine clinically meaningful outcomes associated with the treatment/management of food allergy. 28,46 The development of patient-reported outcome measures and assessment tools is a complex science that requires testing for multiple measures including validity (particularly construct validity), reliability/reproducibility, usability, feasibility, internal consistency, responsiveness, and interpretability to ensure that outcome measures are psychometrically sound, person-centered, meaningful, amenable to change (ie, before and after treatment), and implementable. 28 Additionally, further study is needed in the translation of HRQoL instruments primarily used in research for use in clinical practice. Because the economic burden of peanut allergy is substantial, measurable HRQoL outcomes can help contextualize treatment benefits to allow payers to better integrate OIT into formularies and treatment continua. 2,47 Heterogeneity in trial design with regard to treatment duration, eligibility criteria, or blinding could have affected HRQoL outcomes.